Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease.
Cellular abnormalities in amyotrophic lateral sclerosis (ALS) are not limited to motor neurons. Astrocyte dysfunction also occurs in human ALS and transgenic rodents expressing mutant human SOD1 protein (SOD1(G93A)). Here we investigated focal enrichment of normal astrocytes using transplantation of lineage-restricted astrocyte precursors, called glial-restricted precursors (GRPs). We transplanted GRPs around cervical spinal cord respiratory motor neuron pools, the principal cells whose dysfunction precipitates death in ALS. GRPs survived in diseased tissue, differentiated efficiently into astrocytes and reduced microgliosis in the cervical spinal cords of SOD1(G93A) rats. GRPs also extended survival and disease duration, attenuated motor neuron loss and slowed declines in forelimb motor and respiratory physiological functions. Neuroprotection was mediated in part by the primary astrocyte glutamate transporter GLT1. These findings indicate the feasibility and efficacy of transplantation-based astrocyte replacement and show that targeted multisegmental cell delivery to the cervical spinal cord is a promising therapeutic strategy for slowing focal motor neuron loss associated with ALS.
Lepore
Angelo C
AC
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Rauck
Britta
B
Dejea
Christine
C
Pardo
Andrea C
AC
Rao
Mahendra S
MS
Rothstein
Jeffrey D
JD
Maragakis
Nicholas J
NJ
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D001253:Astrocytes / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D017690:Cell Transplantation; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000172:deficiency; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D006614:Hindlimb / Q000503:physiopathology; D006801:Humans; D008840:Microfilament Proteins; D016472:Motor Neuron Disease / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D018482:Muscle, Skeletal / Q000503:physiopathology; D009431:Neural Conduction / Q000235:genetics; D010791:Phrenic Nerve / Q000503:physiopathology; D051381:Rats; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D013234:Stem Cells / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics
C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D049452:Green Fluorescent Proteins; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase